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Background: Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have a higher risk of osteoporosis/fractures; however, the causal relationship remains unclear. Methods: Publicly available genome‐wide association studies (GWASs) were used for Mendelian randomization (MR) analysis. GWASs of NAFLD and fractures were obtained from the FinnGen Consortium. GWASs of bone mineral density (BMD) were derived from a meta‐analysis. GWASs of obesity, diabetes, liver function, and serum lipid‐related metrics were used to clarify whether the accompanying NAFLD symptoms contributed to fractures. Moreover, two additional GWASs of NAFLD were applied. Results: A causal association was not observed between NAFLD and BMD using GWASs from the FinnGen Consortium. However, a causal relationship between NAFLD and femoral neck‐BMD (FN‐BMD), a suggestive relationship between fibrosis and FN‐BMD, and between NAFLD and osteoporosis were identified in replication GWASs. Genetically proxied body mass index (BMI), high‐density lipoprotein (HDL), and hip circumference increased the likelihood of lower limb fractures. The waist‐to‐hip ratio decreased, whereas glycated hemoglobin (HbA1C) and homeostasis model assessment of β‐cell function (HOMA‐B) increased the risk of forearm fractures. Low‐density lipoprotein (LDL) reduced, whereas HbA1C increased the incidence of femoral fractures. Alkaline phosphatase (ALP) raised the risk of foot fractures. However, after a multivariate MR analysis (adjusted for BMI), all the relationships became insignificant. Conclusions: NAFLD caused reduced BMD, and genetically predicted HDL, LDL, HbA1C, HOMA‐B, ALP, hip circumference, and waist‐to‐hip ratio causally increased the risk of fractures. BMI may mediate causal relationships. Larger GWASs are required to verify this finding. [ABSTRACT FROM AUTHOR]

Ectopic fat deposition in the liver, known as non-alcoholic fatty liver disease (NAFLD), affects up to 30% of the worldwide population. miRNA-122, the most abundant liver-specific miRNA, protects hepatic steatosis and inhibits cholesterol and fatty acid synthesis in NAFLD. Previously, we have shown that compared with its expression in healthy controls, miRNA-122 decreased in the liver tissue but gradually increased in the serum of patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, suggesting that miRNA-122 could have been transported to the serum. Here, we aimed to confirm and unravel the mechanism of transportation of miRNA-122 to extra-hepatocytes. Our findings showed a decrease in the intra-hepatocyte miRNA-122 and an increase in the extra-hepatocyte (medium level) miRNA-122, suggesting the miRNA-122 "escaped" from the intra-hepatocyte due to an increased extra-hepatocyte excretion. Using bioinformatics tools, we showed that miRNA-122 binds to circPI4KB, which was further validated by an RNA pull-down and luciferase reporter assay. The levels of circPI4KB in intra- and extra-hepatocytes corresponded to that of miRNA-122, and the overexpression of circPI4KB increased the miRNA-122 in extra-hepatocytes, consequently accomplishing a decreased protective role of miRNA-122 in inhibiting the lipid deposition. The present study provides a new explanation for the pathogenesis of the hepatic lipid deposition in NAFLD. [ABSTRACT FROM AUTHOR]

Background and Aim: There is debate among the hepatology community regarding the simple non‐invasive scoring systems and histological scores (even it was developed for histological classification) in predicting clinical outcomes in patients with non‐alcoholic fatty liver disease (NAFLD). This study aimed to determine whether the presence of simple non‐invasive scoring systems and histological scores could predict all‐cause mortality, liver‐related mortality, and liver disease decompensation (liver failure, cirrhosis, hepatocellular carcinoma, or decompensated liver disease). Methods: The pooled hazard ratio of prognostic factors and incidence rate per 1000 person‐years in patients with NAFLD was calculated and further adjusted by two different models of handling the duplicated data. Results: A total of 19 longitudinal studies were included. Most simple non‐invasive scoring systems (Fibrosis‐4 Score, BARD, and aspartate aminotransferase‐to‐platelet ratio index) and histological scores (NAFLD activity score, Brunt, and "steatosis, activity, and fibrosis") failed in predicting mortality, and only the NAFLD fibrosis score > 0.676 showed prognostic ability to all‐cause mortality (four studies, 7564 patients, 118 352 person‐years followed up, pooled hazard ratio 1.44, 95% confidence interval [CI] 1.05–1.96). The incidence rate per 1000 person‐years of all‐cause mortality, liver‐related mortality, cardiovascular‐related mortality, and liver disease decompensation resulted in a pooled incidence rate per 1000 person‐years of 22.65 (14 studies, 95% CI 9.62–53.31), 3.19 (7 studies, 95% CI 1.14–8.93), 6.02 (6 studies, 95% CI 4.69–7.74), and 11.46 (4 studies, 95% CI 5.33–24.63), respectively. Conclusion: Non‐alcoholic fatty liver disease fibrosis score showed promising prognostic value to all‐cause mortality. Most present simple non‐invasive scoring systems and histological scores failed to predict clinical outcomes. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • miRNA-34a, miRNA-122 and miRNA-192 helped to distinguish NAFLD and NASH severity. • The correlation of miRNA expression between serum and liver tissue was inconsistent. • miRNA-122 showed moderate accuracy to distinguish NAFLD from healthy controls. • miRNA-34a showed moderate accuracy to distinguish NASH from NAFL. Background & Aims microRNAs (miRNAs) are deregulated in non-alcoholic fatty liver disease (NAFLD) and have been proposed as useful markers for the diagnosis and stratification of disease severity. We conducted a meta-analysis to identify the potential usefulness of miRNA biomarkers in the diagnosis and stratification of NAFLD severity. Methods After a systematic review, circulating miRNA expression consistency and mean fold-changes were analysed using a vote-counting strategy. The sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio and area under the curve (AUC) for the diagnosis of NAFLD or non-alcoholic steatohepatitis (NASH) were pooled using a bivariate meta-analysis. Deeks' funnel plot was used to assess the publication bias. Results Thirty-seven studies of miRNA expression profiles and six studies of diagnostic accuracy were ultimately included in the quantitative analysis. miRNA-122 and miRNA-192 showed consistent upregulation. miRNA-122 was upregulated in every scenario used to distinguish NAFLD severity. The miRNA expression correlation between the serum and liver tissue was inconsistent across studies. miRNA-122 distinguished NAFLD from healthy controls with an AUC of 0.82 (95% CI 0.75–0.89), and miRNA-34a distinguished non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver (NAFL) with an AUC of 0.78 (95% CI 0.67–0.88). Conclusion miRNA-34a, miRNA-122 and miRNA-192 were identified as potential diagnostic markers to segregate NAFL from NASH. Both miRNA-122, in distinguishing NAFLD from healthy controls, and miRNA-34a, in distinguishing NASH from NAFL, showed moderate diagnostic accuracy. miRNA-122 was upregulated in every scenario of NAFL, NASH and fibrosis. Lay summary microRNAs are deregulated in non-alcoholic fatty liver disease. The microRNAs, miRNA-34a, miRNA-122 and miRNA-192, were identified as potential biomarkers of non-alcoholic fatty liver and non-alcoholic steatohepatitis, at different stages of disease severity. The correlation between miRNA expression in the serum and in liver tissue was inconsistent, or even inverse. [ABSTRACT FROM AUTHOR]

Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH). PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model. We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs. When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking. Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring. [Display omitted] • This is the largest systematic review of imaging/elastography biomarkers in NAFLD. • Meta-analysis of 1 MR elastography and 3 ultrasound techniques. • Elastography may help in fibrosis evaluation in those with NAFLD and valid readings. • Clinical utility of these tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified cut-offs are lacking. [ABSTRACT FROM AUTHOR]